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The Impact of Host Factors on the Re...

Le, Catherine Thuy Khanh.

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The Impact of Host Factors on the Regulation of the Pd-1/Pd-L1 Pathway on T Cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Impact of Host Factors on the Regulation of the Pd-1/Pd-L1 Pathway on T Cells./
Author:	Le, Catherine Thuy Khanh.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	155 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27741966
ISBN:	9798645486945

The Impact of Host Factors on the Regulation of the Pd-1/Pd-L1 Pathway on T Cells.
Le, Catherine Thuy Khanh.

The Impact of Host Factors on the Regulation of the Pd-1/Pd-L1 Pathway on T Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 155 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--University of California, Davis, 2020.

This item must not be sold to any third party vendors.

The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade and long-term impact on T-cell homeostasis remain unclear. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these laboratory mice present with a vastly restricted immune profile compared to humans and do not mirror the average cancer patient found in the clinic. This dissertation aims to modify the preclinical mouse model to incorporate host-modifying factors of obesity and age to address important questions on the role of host factors on regulating the PD-1/PD-L1(2) pathway. Here, we discuss the caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario. We show that diet-induced obesity impairs naive T-cell responses to antigen, using the model of Experimental Autoimmune Encephalomyelitis (EAE), through upregulation of the PD-1/PD-L1 pathway on innate cells, such as DCs, and this impairment is reversed by PD-1 blockade. We also show that the age-associated increase of PD-1 on the T-cell memory compartment can regulate their bystander activation, a non-antigen-specific T-cell response mediated by high-levels of cytokines. PD-1 negative cells had greater responses to cytokine alone stimulation but also greater activation-induced cell apoptosis. PD-1 blockade or deficiency resulted in heightened bystander activation but also cell loss of the memory compartment. These studies highlight the importance of PD-1 as a global negative regulator of T-cell homeostasis and how modifying the preclinical model to better reflect the human condition can shed new light and perspectives on T-cell biology.

ISBN: 9798645486945Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Age

The Impact of Host Factors on the Regulation of the Pd-1/Pd-L1 Pathway on T Cells.
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